Background There are over 2000 pregnancies annually in women with type 1 diabetes in the UK. Despite recent improvements in diabetes technology, most women cannot achieve and maintain the recommended ...pregnancy glucose targets. Thus, one in two babies experience complications requiring neonatal care unit admission. Recent studies demonstrate that hybrid closed-loop therapy, in which algorithms adjust insulin delivery according to continuous glucose measurements, is effective for managing type 1 diabetes outside of pregnancy, but efficacy during pregnancy is unclear. Objective To examine the clinical efficacy of hybrid closed-loop compared to standard insulin therapy in pregnant women with type 1 diabetes. Design A multicentre, parallel-group, open-label, randomised, controlled trial in pregnant women with type 1 diabetes. Setting Nine antenatal diabetes clinics in England, Scotland and Northern Ireland. Participants Pregnant women with type 1 diabetes and above-target glucose levels, defined as glycated haemoglobin A1c of ≥ 48 mmol/mol (6.5%) in early pregnancy. Interventions A hybrid closed-loop system compared to standard insulin delivery (via insulin pump or multiple daily injections) with continuous glucose monitoring. Outcome measures The primary outcome is the difference between the intervention and control groups in percentage time spent in the pregnancy glucose target range (3.5–7.8 mmol/l) as measured by continuous glucose monitoring from 16 weeks’ gestation until delivery. Secondary outcomes include overnight time in range, time above range (> 7.8 mmol/l), glycated haemoglobin A1c, safety outcomes (diabetic ketoacidosis, severe hypoglycaemia, adverse device events), psychosocial functioning obstetric and neonatal outcomes. Results The percentage of time that maternal glucose levels were within target range was higher with closed-loop than standard insulin therapy: 68.2 ± 10.5 in closed-loop and 55.6 ± 12.5 in the control group (mean‑adjusted difference 10.5 percentage points, 95% confidence interval 7.0 to 14.0; p < 0.001). Results were consistent in secondary outcomes, with less time above range (−10.2%, 95% confidence interval −13.8 to −6.6%; p < 0.001), higher overnight time in range (12.3%, 95% confidence interval 8.3 to 16.2%; p < 0.001) and lower glycated haemoglobin A1c (−0.31%, 95% confidence interval −0.50 to −0.12%; p < 0.002) all favouring closed-loop. The treatment effect was apparent from early pregnancy and consistent across clinical sites, maternal glycated haemoglobin A1c categories and previous insulin regimen. Maternal glucose improvements were achieved with 3.7 kg less gestational weight gain and without additional hypoglycaemia or total daily insulin dose. There were no unanticipated safety problems (six vs. five severe hypoglycaemia cases, one diabetic ketoacidosis per group) and seven device-related adverse events associated with closed-loop. There were no between-group differences in patient-reported outcomes. There was one shoulder dystocia in the closed-loop group and four serious birth injuries, including one neonatal death in the standard care group. Limitations Our results cannot be extrapolated to closed-loop systems with higher glucose targets, and our sample size did not provide definitive data on maternal and neonatal outcomes. Conclusions Hybrid closed-loop therapy significantly improved maternal glycaemia during type 1 diabetes pregnancy. Our results support National Institute for Health and Care Excellence guideline recommendations that hybrid closed-loop therapy should be offered to all pregnant women with type 1 diabetes. Future work Future trials should examine the effectiveness of hybrid closed-loop started before pregnancy, or as soon as possible after pregnancy confirmation. Trial registration This trial is registered as ISRCTN56898625. Funding This award was funded by the National Institute of Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/35/01) and is published in full in Efficacy and Mechanism Evaluation ; Vol. 11, No. 7. See the NIHR Funding and Awards website for further award information. Dexcom supplied the continuous glucose monitoring systems used by AiDAPT intervention- and control-arm participants at reduced cost.
Background
Hyperglycaemia and hypoglycaemia are common in preterm infants and are associated with increased mortality and morbidity. Continuous glucose monitoring is widely used to target glucose ...control in adults and children, but not in neonates.
Objective
To evaluate the role of continuous glucose monitoring in the preterm infant.
Design
The REAl-time Continuous glucose moniToring in neonatal intensive care project combined (1) a feasibility study, (2) a multicentre randomised controlled trial and (3) a pilot of ‘closed-loop’ continuous glucose monitoring. The feasibility study comprised a single-centre study (
n
= 20). Eligibility criteria included a birthweight ≤ 1200 g and aged ≤ 48 hours. Continuous glucose monitoring was initiated to support glucose control. The efficacy and safety outcomes guided the design of the randomised controlled trial. The randomised controlled trial comprised a European multicentre trial (
n
= 182). Eligibility criteria included birthweight ≤ 1200 g and aged ≤ 24 hours. Exclusion criteria included any lethal congenital abnormality. Continuous glucose monitoring was initiated to support glucose control within 24 hours of birth. In the intervention group, the continuous glucose monitoring sensor provided real-time data on glucose levels, which guided clinical management. In control infants, the continuous glucose monitoring data were masked, and glucose level was managed in accordance with standard clinical practice and based on the blood glucose levels. The primary outcome measure was the percentage of time during which the sensor glucose level was within the target range of 2.6–10 mmol/l. Secondary outcome measures included mean sensor glucose level, the percentage of time during which the sensor glucose level was within the target range of 4–8 mmol/l, the percentage of time during which the sensor glucose level was in the hyperglycaemic range (i.e. > 15 mmol/l) and sensor glucose level variability. Safety outcomes included hypoglycaemia exposure. Acceptability assessment and health economic analyses were carried out and further exploratory health outcomes were explored. The mean percentage of time in glucose target range of 2.6–10 mmol/l was 9% higher in infants in the continuous glucose monitoring group (95% confidence interval 3% to 14%;
p
= 0.002), and the mean time in the target range of 4–8 mmol/l was 12% higher in this group (95% confidence interval 4% to 19%;
p
= 0.004). There was no difference in the number of episodes of hypoglycaemia. Exploratory outcomes showed a reduced risk of necrotising enterocolitis in the intervention arm (odds ratio 0.33, 95% confidence interval 0.13 to 0.78;
p
= 0.01). Health economic analyses demonstrated that continuous glucose monitoring was cost-effective on the basis of the cost per additional case of adequate glucose control between 2.6 and 10 mmol/l. The ‘closed-loop’ study was a single-center pilot study, with eligibility criteria including a birthweight of ≤ 1200 g and aged ≤ 48 hours. Infants underwent continuous glucose monitoring for the first week of life (
n
= 21), with those in the intervention group receiving closed-loop insulin delivery between 48 and 72 hours of age. The primary outcome of percentage of time in the target range (i.e. sensor glucose 4–8 mmol/l) increased from a median of 26% (interquartile range 6–64%) to 91% (interquartile range 78–99%) during closed-loop insulin delivery (
p
< 0.001).
Limitations
These studies have not defined the optimal targets for glucose control or the best strategies to achieve them in these infants.
Future work
Studies are needed to evaluate the longer-term impact of targeting glucose control on clinical outcomes.
Conclusions
Continuous glucose monitoring in extremely preterm infants can improve glucose control, with closed-loop insulin delivery having further potential to target glucose levels. Staff and parents felt that the use of continuous glucose monitoring improved care and the results of the health economic evaluation favours the use of continuous glucose monitoring.
Trial registration
Current Controlled Trials ISRCTN12793535.
Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in
Efficacy and Mechanism Evaluation
; Vol. 8, No. 16. See the NIHR Journals Library website for further project information. Medtronic plc provided some MiniMed™ 640G systems and Nova Biomedical (Waltham, MA, USA) provided point-of-care devices.
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Insulin replacement therapy is integral to the management of type 1 diabetes, which is characterised by absolute insulin deficiency. Optimal glycaemic control, as assessed by glycated ...haemoglobin, and avoidance of hyper- and hypoglycaemic excursions have been shown to prevent diabetes-related complications. Insulin pump use has increased considerably over the past decade with beneficial effects on glycaemic control, quality of life and treatment satisfaction. The advent and progress of ambulatory glucose sensor technology has enabled continuous glucose monitoring based on real-time glucose levels to be integrated with insulin therapy. Low glucose and predictive low glucose suspend systems are currently used in clinical practice to mitigate against hypoglycaemia, and provide the first step towards feedback glucose control. The more advanced technology approach, an artificial pancreas or a closed-loop system, gradually increases and decreases insulin delivery in a glucose-responsive fashion to mitigate against hyper- and hypoglycaemia. Randomised outpatient clinical trials over the past 5 years have demonstrated the feasibility, safety and efficacy of the approach, and the recent FDA approval of the first single hormone closed-loop system establishes a new standard of care for people with type 1 diabetes.
Intensive insulin therapy aimed at achieving normal glucose levels significantly reduces the complications that are associated with diabetes but is also associated with an increased risk of low ...glucose levels (hypoglycemia). The growing use of continuous glucose monitors has stimulated the development of the artificial pancreas, a closed-loop insulin-delivery system aimed at restoring near-normal glucose levels while reducing the risk of hypoglycemia. The artificial pancreas comprises three components: a continuous glucose monitor, an insulin infusion pump and a control algorithm delivering insulin according to real-time glucose readings. In this article, we review closed-loop glucose control, including its components, development, testing and clinical application.
AbstractObjectiveTo evaluate the efficacy and safety of artificial pancreas treatment in non-pregnant outpatients with type 1 diabetes.DesignSystematic review and meta-analysis of randomised ...controlled trials.Data sourcesMedline, Embase, Cochrane Library, and grey literature up to 2 February 2018.Eligibility criteria for selecting studiesRandomised controlled trials in non-pregnant outpatients with type 1 diabetes that compared the use of any artificial pancreas system with any type of insulin based treatment. Primary outcome was proportion (%) of time that sensor glucose level was within the near normoglycaemic range (3.9-10 mmol/L). Secondary outcomes included proportion (%) of time that sensor glucose level was above 10 mmol/L or below 3.9 mmol/L, low blood glucose index overnight, mean sensor glucose level, total daily insulin needs, and glycated haemoglobin. The Cochrane Collaboration risk of bias tool was used to assess study quality.Results40 studies (1027 participants with data for 44 comparisons) were included in the meta-analysis. 35 comparisons assessed a single hormone artificial pancreas system, whereas nine comparisons assessed a dual hormone system. Only nine studies were at low risk of bias. Proportion of time in the near normoglycaemic range (3.9-10.0 mmol/L) was significantly higher with artificial pancreas use, both overnight (weighted mean difference 15.15%, 95% confidence interval 12.21% to 18.09%) and over a 24 hour period (9.62%, 7.54% to 11.7%). Artificial pancreas systems had a favourable effect on the proportion of time with sensor glucose level above 10 mmol/L (−8.52%, −11.14% to −5.9%) or below 3.9 mmol/L (−1.49%, −1.86% to −1.11%) over 24 hours, compared with control treatment. Robustness of findings for the primary outcome was verified in sensitivity analyses, by including only trials at low risk of bias (11.64%, 9.1% to 14.18%) or trials under unsupervised, normal living conditions (10.42%, 8.63% to 12.2%). Results were consistent in a subgroup analysis both for single hormone and dual hormone artificial pancreas systems.ConclusionsArtificial pancreas systems are an efficacious and safe approach for treating outpatients with type 1 diabetes. The main limitations of current research evidence on artificial pancreas systems are related to inconsistency in outcome reporting, small sample size, and short follow-up duration of individual trials.
The role of automated insulin delivery systems in diabetes is expanding. Hybrid closed-loop systems are being used in routine clinical practice for treating people with type 1 diabetes. ...Encouragingly, real-world data reflects the performance and usability observed in clinical trials. We review the commercially available hybrid closed-loop systems, their distinctive features and the associated real-world data. We also consider emerging indications for closed-loop systems, including the treatment of type 2 diabetes where variability of day-to-day insulin requirements is high, and other challenging applications for this technology. We discuss issues around access and implementation of closed-loop technology, and consider the limitations of present closed-loop systems, as well as innovative approaches that are being evaluated to improve their performance.
Advances in artificial pancreas systems Boughton, Charlotte K; Hovorka, Roman
Science translational medicine,
03/2019, Letnik:
11, Številka:
484
Journal Article
Recenzirano
Odprti dostop
The artificial pancreas for managing type 1 diabetes has progressed from research into clinical practice, revealing areas for future advancements.
Introduction: Nocturnal glucose control remains challenging in children and adolescents with type 1 diabetes due to highly variable overnight insulin requirements. The issue may be addressed by ...glucose responsive insulin delivery based on real-time continuous glucose measurements.
Areas covered: This review outlines recent developments of glucose responsive insulin delivery systems from a paediatric perspective. We cover threshold-based suspend application, predictive low glucose suspend, and more advanced single hormone and dual-hormone closed-loop systems. Approaches are evaluated in relation to nocturnal glucose control particularly during outpatient randomised controlled trials.
Expert opinion: Significant progress translating research from controlled clinical centre settings to free-living unsupervised home studies have been achieved over the past decade. Nocturnal glycaemic control can be improved whilst reducing the risk of hypoglycaemia with closed-loop systems. Following the US regulatory approval of the first hybrid closed-loop system in non-paediatric population, large multinational closed-loop clinical trials and pivotal studies including paediatric populations are underway or in preparation to facilitate the use of closed-loop systems in clinical practice.
Abstract Background The closed-loop system (artificial pancreas) delivers insulin in a glucose-responsive manner by the use of a control algorithm that automatically directs insulin delivery, based ...on real-time sensor glucose concentrations. Results from hospital-based studies have shown improved overnight glucose control and reduced risk of hypoglycaemia in type 1 diabetes. We aimed to assess whether unsupervised closed-loop systems can provide a realistic treatment option in patients with type 1 diabetes. Methods We combined data from two open-label, phase 2, randomised, cross-over, unsupervised home trials of people with type 1 diabetes, one in 24 adults (mean age 43 years SD 12, HbA1c 8·0% 0·9) and the other in 16 adolescents (15·6 3·6, 8·1 0·8). In each trial, after training on study devices, participants were allocated to two periods of sensor-augmented pump therapy either with or without overnight closed loop that used a model predictive control algorithm to direct insulin delivery. Allocation sequence was done with a computer-generated random code. Each period lasted 4 weeks in adults and 3 weeks in adolescents. Primary outcome for both trials was time when sensor glucose was in the target range (3·9–8·0 mmol/L). Analysis was by intention to treat. Participants (or parents) gave written informed consent. The trials are registered with ClinicalTrials.gov , numbers NCT01440140 and NCT01221467. Findings Closed loop was started by participants on their own volition on 866 (89%) of 978 nights. The proportion of time when sensor glucose was in the target range between 0000 h and 0800 h was increased by a mean of 18·4% (95% CI 13·5–23·4, p<0·0001) during closed loop compared with no closed loop. Closed loop significantly reduced mean overnight sensor glucose by 0·9 mmol/L (95% CI 0·4–1·3, p=0·0001), and reduced the proportion of time when sensor glucose values were suggestive of hyperglycaemia (>8·0 mmol/L) (15·9%, 10·7–21·0; p<0·0001) and hypoglycaemia (<3·9 mmol/L) (median 0·9, IQR 0·2–2·2; p=0·014). Lower mean overnight glucose was associated with increased overnight insulin delivery (p<0·0001) without changing total daily insulin amount (p=0·84). Interpretation Extended use of overnight closed loop at home without supervision is feasible in adults and adolescents with type 1 diabetes. Clinically significant reduction in overnight glucose was observed accompanied by reduced time spent by patients in hypoglycaemia. To our knowledge, such combined effect has not been documented with any other means of intensified conventional insulin delivery. Longer term studies are warranted to assess its clinical potential. Funding Diabetes UK, Juvenile Diabetes Research Foundation, NIHR Cambridge Biomedical Research Centre.
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